DE19811559A1 - New substituted derivatives of cyclooctadepsipeptide PF1022, useful as parasiticides, especially anthelmintics - Google Patents

Abstract

Benzene ring-substituted PF1022 derivative cyclooctadepsipeptides are new. Cyclooctadepsipeptides (I) of formula (A; A1 = R1; A2 = R2) are new. R1 = CN or C-C bonded heterocyclyl; or alkenyl, alkynyl or aryl (all optionally substituted); R2 = H or the same as R1. Independent claims are included for: (1) new intermediates (II) of formula (A; A1 = X1; A2 =X2); and (2) methods for the preparation of (I) and (II). X1 = Br, I or OSO2Rf; Rf = fluorinated 1-4C alkyl; X2 = H or the same as X1.

Description

The invention relates to new cyclooctadepsipeptides, processes for their preparation and their use for controlling parasites, especially helminths in the Animal and human medicine and intermediates for their manufacture.

Various cyclodepsipeptides with antiparasitic activity are known in the literature wrote. EP 382 173 A2 describes a cyclooctadepsipeptide PF1022 known. From EP 626 376 A1, EP 634 408 A1 and EP 718 293 A1 further 24-membered cyclodepsipeptides known. The anthelmintic effect of which is not satisfactory in all cases.

1. New cyclooctadepsipeptides of the formula (I)

found in which
R ^{1 is} cyano, CC-linked heterocyclyl or optionally substituted alkenyl, alkynyl or aryl and
R ^{2 represents} hydrogen or the same radical as R ¹ .

2. A process for the preparation of the compounds of formula (I)

in which R ¹ and R ^{2 have} the meanings given above,
found, characterized in that compounds of the formula (II)

in which
X ^{1 represents} bromine, iodine, -O-SO ₂ -R ^f , amino or -N ₂ ⁺ (X ³ ) ⁻, wherein
R ^{f represents} fluorinated C ₁ -C ₄ alkyl and
X ^{3 stands} for a diazonium salt stabilizing anion such as tetrafluoroborate and
X ^{2 represents} hydrogen or the same radical as X ¹ ,
with a suitable reagent which splits off the group R ¹ in the presence of a transition metal catalyst with CC linkage.

3. The cyclooctadepsipeptides of the formula (II) in which X ^{1 is} bromine, iodine, -OSO ₂ R ^f - where R ^{f is} fluorinated C ₁ -C ₄ -alkyl are new and are the subject of the present invention.

4. The new compounds of formula (II) are obtained by

• a) in the case of bromo-substituted cyclooctadepsipeptides of the formula (II-a)
  in which
  X ^{2-1 represents} hydrogen or bromine,
  the cyclooctadepsipeptide called PF1022
  brominated or
• b) in the case of iodinated cyclooctadepsipeptides of the formula (II-b)
  in which
  X ^{2-2 represents} hydrogen or iodine,
  iodines the cyclooctadepsipeptide designated PF1022 or
• c) in the case of sulfonic acid cyclooctadepsipeptide esters of the formula (II-c)
  in which
  R ^{f represents} fluorinated C ₁ -C ₄ alkyl and
  X ^{2-3 stands} for hydrogen or for -O-SO ₂ -R ^f ,
  hydroxy-substituted cyclooctadepsipeptides of the formula (III)
  in which
  X ^{3 represents} hydroxy or hydrogen,
  with sulfonic anhydrides or halides of the formula (IV)
  R ^f -SO ₂ -Y (IV),
  in which
  Y represents -O-SO ₂ -R ^f , F or chlorine,
  in the presence of an acid binder, or
• d) in the case of sulfonic acid cyclooctadepsipeptide esters of the formula (II-c) diazotized amino-substituted cyclooctadepsipeptide of the formula (V)
  in which
  X ^{4 represents} -N ₂ ⁺ (X ³ ) ⁻ or hydrogen,
  X ^{3 represents} a diazominium salt stabilizing anion,
  in the presence of a sulfonic acid of formula (VI)
  HO-SO ₂ -R ^f (VI),
  in which R ^{f has} the meaning given above,

implements.

5. It has also been found that the compounds of the formula (I) are outstanding are suitable for combating helminths in human and veterinary medicine

The new cyclooctadepsipeptides are general by the formulas (I) and (II) Are defined.

The substituents X ¹ and X ² or R ¹ and R ² are preferably in the para or ortho position. The para position is particularly preferred.

Preferred compounds of the formula (I) are those in which:
R ¹ for cyano, C ₅ -C ₈ cycloalkenyl, CC-linked 5- to 10-membered, optionally mono- or polyunsaturated heterocyclyl with one or more heteroatoms of the series oxygen or nitrogen, if appropriate by C ₁ -C ₄ -Alkyl, benzyl, C ₁ -C ₄ alkylcarbonyl or t-butoxycarbonyl is substituted, a radical of the series -C (R ³ ) = CH ₂ , -CH = CR ⁴ R ⁵ , -CH = C (R ⁶ ) CO ₂ R ⁷ or -C∼CR ⁸ or, if necessary, single or multiple times independently of one another by nitro, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₄ alkenyl, C ₁ -C ₄ haloalkyl, hydroxy, C ₁ -C ₆ alkoxy, C ₁ -C ₄ halo alkoxy, tetrahydropyranyloxy, amino, morpholino, piperidino, di- (C ₁ -C ₄ alkyl) amino, C ₁ -C ₃ alkylcarbonylamino, C ₁ -C ₄ -Alkoxycarbonylamino, benzyloxycarbonylamino, carboxy, C ₁ -C ₄ -alkoxycarbonyl or phenyl-substituted phenyl or naphthyl, where
R ^{3 represents} C ₁ -C ₄ alkoxy or C ₁ -C ₄ alkylcarbonyloxy,
R ^{4 represents} cyano or C ₁ -C ₄ alkyl,
R ⁵ and R ⁶ each represent hydrogen or methyl,
R ⁷ for C ₁ -C ₁₂ alkyl, single or multiple by halogen or simply by cyano, hydroxy, C ₁ -C ₄ alkoxy, C ₁ -C ₄ dialkylamino or three- to eight-membered cyclic amino (= C ₂ - C ₇ alkylene amino, where a methylene group can be replaced by an oxygen, sulfur or nitrogen atom) substituted C ₂ -C ₁₂ alkyl, for (tetra hydro) furfuryl, C ₃ -C ₆ -2 alkenyl, C ₃ -C ₈ cycloalkyl, optionally substituted by halogen-substituted phenyl or benzyl and
R ^{8 is} C ₁ -C ₁₂ alkyl, C ₃ -C ₈ cycloalkyl, C ₁ -C ₈ hydroxyalkyl, C ₁ -C ₄ alkoxy-C ₁ -C ₈ alkyl, tetrahydropyranyloxy-C ₁ -C ₄ -alkyl, 1-hydroxy- C ₃ -C ₈ -cycloalkyl, α-amino-C ₁ -C ₈ -alkyl, α-C ₁ -C ₄ -alkylamino carboryl-amino-C ₁ -C ₄ -alkyl, carboxy- C ₁ -C ₁₁ alkyl, C ₁ -C ₄ alkoxy carbonyl-C ₁ -C ₁₁ alkyl, phenoxycarbonyl-C ₁ -C ₁₁ alkyl, tri (C ₁ -C ₄ alkyl) silyl, C ₁ - C ₁₁ alkylcarbonyl, optionally substituted by halogen, phenyl-C ₁ -C ₄ -alkyl or α-hydroxybenzyl.

R ² represents hydrogen or one of the radicals specified for R ¹ .

Compounds of the formula (I) in which:
R ¹ for cyano, C ₅ -C ₈ cycloalkenyl, CC-linked 5- to 6-membered, optionally mono- to tri-unsaturated heterocyclyl with one or two heteroatoms from the series oxygen or nitrogen, which is optionally substituted by C ₁ -C ₄ -Alkyl, benzyl, C ₁ -C ₄ -alkylcarbonyl or t-butoxycarbonyl-substituted nitrogen atoms, one of the radicals -C (R ³ ) = CH ₂ , -CH = CR ⁴ R ⁵ , -CH = C (R ⁶ ) CO ₂ R ⁷ or -C∼CR ⁸ or for optionally up to four times independently of one another by nitro, fluorine, chlorine, bromine, C ₁ -C ₄ alkyl, C ₂ - C ₄ alkenyl, hydroxy, C ₁ -C ₄ - Alkoxy, tetrahydropyranyloxy, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy substituted by fluorine or chlorine, amino, morpholino, piperidino, di- (C ₁ -C ₄ alkyl) amino, C ₁ -C ₃ -Alkylcarbonylamino, C ₁ -C ₄ - alkoxycarbonylamino, benzyloxycarborylamino, carboxy, C ₁ -C ₄ alkoxy carbonyl or phenyl substituted phenyl or naphthyl, where
R ^{3 represents} C ₁ -C ₄ alkoxy or C ₁ -C ₄ alkylcarbonyloxy,
R ^{4 represents} cyano or C ₁ -C ₄ alkyl,
R ⁵ and R ⁶ each represent hydrogen or methyl,
R ⁷ for C ₁ -C ₈ alkyl, nC ₉ -C ₁₂ alkyl, mono- or polysubstituted by fluorine-substituted C ₂ -C ₆ alkyl or nC ₇ -C ₁₂ alkyl, or in the 2-position by chlorine, bromine , Cyano hydroxy, C ₁ -C ₄ alkoxy, C ₁ -C ₄ dialkyl amino or five- to six-membered cyclic amino (= C ₄ -C ₅ -alkylene amino, where a methylene group through an oxygen, sulfur or nitrogen atom can be replaced) substituted ethyl, (tetrahydro) furfuryl, C ₃ -C ₆ -2-alkenyl, C ₃ -C ₈ cycloalkyl, optionally substituted by fluorine, chlorine or bromine, and phenyl or benzyl and
R ^{8 is} C ₁ -C ₄ -alkyl, nC ₅ -C ₁₂ -alkyl, C ₅ -C ₆ -cycloalkyl, -hydroxy-C ₁ -C ₈ -alkyl, ω-hydroxy-nC ₂ -C ₈ -alkyl, α-C ₁ -C ₄ alkoxy-C ₁ -C ₈ alkyl, ω-tetrahydropyranyloxy-nC ₁ -C ₄ alkyl, 1-hydroxy-C ₃ -C ₆ cycloalkyl, α-amino-C ₁ -C ₈ -alkyl, α-C ₁ -C ₄ -alkylaminocarbonylamino-C ₁ -C ₃ -alkyl, ω-carboxy-nC ₁ -C ₁₁ -alkyl, C ₁ -C ₄ -alkoxycarbonyl-nC ₁ -C ₁₁ -alkyl, Phenoxycarbonyl-C ₁ -C ₁₁ alkyl, tri (C ₁ -C ₄ ) alkylsilyl, C ₁ -C ₅ alkylcarbonyl, nC ₆ -C ₁₁ alkylcarbonyl, optionally substituted by fluorine, chlorine or bromine, phenyl-C ₁ -C _2- alkyl or α-hydroxy benzyl.

R ² represents hydrogen or one of the radicals specified for R ¹ .

Compounds of the formula (I) in which:
R ¹ for cyano, 1-cyclopentenyl, 2-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, furyl, dihydrofuryl, optionally substituted by methyl, benzyl, acetyl, propionyl or t-butoxycarbonyl, N-substituted 2- or 3-pyrrolyl, pyrroline - 2-yl, for dihydropyranyl, 1,3-dioxinyl, one of the radicals -C (R ³ ) = CH ₂ , -CH = CR ⁴ R ⁵ , -CH = C (R ⁶ ) CO ₂ R ⁷ or -C ∼CR ⁸ or for optionally one to three times independently of one another by nitro, fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, 1-propene -1-yl, 1-buten-1-yl, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.-butoxy, tert.-butoxy, tetrahydropyranyloxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy, Chlorodifluoromethoxy, amino, morpholino, piperidino, dimethylamino, diethylamino, dipropyl amino, diisopropylamino, acetylamino, propionylamino, methoxycarbon ylamino, ethoxycarbonylamino, benzyloxycarbonylamino, carboxy, methoxy carbonyl, ethoxycarbonyl, n-propoxyca rbonyl, isopropoxycarbonyl, n-but oxycarbonyl, isobutoxycarbonyl, sec.-butoxycarbonyl, tert.-butoxy or phenyl substituted phenyl, where
R ^{3 represents} methoxy, ethoxy, n-propoxy, isopropoxy, acetyloxy or propionyloxy,
R ^{4 represents} cyano or C ₁ -C ₄ alkyl,
R ⁵ and R ⁶ each represent hydrogen or methyl,
R ⁷ for methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, neo-pentyl, n-pentyl, 2-ethylbutyl, n-hexyl, n-heptyl, 2 -Ethylhexyl, n-octyl, n-nonyl, n-decyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, 1,1,1,3,3,3-hexafluoroisopropyl, heptafluoroisopropyl, 2,2,3, 3, 4,4-hexafluorobutyl, 2-chloroethyl, 2-bromoethyl, 2-cyanoethyl, 2-hy droxyethyl, 2-methoxymethyl, 2-ethoxymethyl, 2-N, N-dimethylamino methyl, 2-N, N-diethylaminomethyl , 2-pyrrolinoethyl, 2-piperidino ethyl, 2-morpholinoethyl, stands for furfuryl, tetrahydrofurfuryl, allyl, 2-butenyl, cyclopentyl, cyclohexyl, optionally single to triple independently of one another substituted by fluorine, chlorine or bromine, phenyl or benzyl and
R ⁸ for methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n -Decyl, cyclopentyl, cyclohexyl, hydroxymethyl, 1-hydroxyethyl, 1-hydroxy- 1-methylethyl, 1-hydroxypropyl, 1-hydroxy-1-methylpropyl, 1-hy droxy-2-methylpropyl, 1-hydroxybutyl, 1-hydroxy- 1,2-dimethylpropyl, 1-hydroxy-3-methylbutyl, 1-hydroxypentyl, 2-ethyl-1-hydroxybutyl, 1-hydroxy-1,3-dimethylbutyl, 1-hydroxy-1,2,2-trimethylpropyl , 1-hydroxyhexyl, 1-hydroxy-1,4-dimethylpentyl, 1-hydroxy-1-isopropyl-2-methylpropyl, 2-ethyl-1-hydroxy-hexyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 5 -Hydroxypentyl, 6-hydroxyhexyl, 2-tetrahydropyranyloxyethyl, 1-hydroxycyclopropyl, 1-hydroxycyclopentyl, 1-hydroxycyclohexyl, 1-aminomethyl, 1-aminoethyl, 1-amino-1-methylethyl, 1-amino-1-ethylpropyl, methylamino carbonyldimethyl , tert-butylaminocarbonyldimethylmethyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carboxypentyl, carboxyhexyl, C arboxyheptyl, carboxyoctyl, phenoxy carbonylmethyl, trimethylsilyl, triethylsilyl, butyldimethylsilyl, triisopropylsilyl, acetyl, propionyl, butyryl, isobutyryl, isovaleryl, caproyl, optionally optionally up to three times independently of one another, fluorine, chlorine or bromine or α-hydroxy-phenyl is α-hydroxyl, phenyl.

R ² represents hydrogen or one of the radicals specified for R ¹ .

Compounds of the formula (II) are preferred in which:
X ^{1 is} bromine, iodine, trifluoromethylsulfonyloxy, nonafluorobutylsulfonyloxy, amino or -N ₂ ⁺ (X ³ ) ^- , where X ^{3 is} tetrafluoroborate;
X ^{2 represents} the radicals indicated at X ¹ or represents hydrogen.

Compounds of the formula (II) in which X ^{1 is} bromine, iodine or trifluoromethylsulfonyloxy and X ^{2 is} hydrogen or one of the radicals indicated at X ¹ are particularly preferred.

Compounds of the formula (II) in which X ^{1 represents} iodine and X ^{2 represents} hydrogen or iodine are very particularly preferred.

If, for example, 8- (2-bromobenzyl) -20- (4-bromobenzyl) -5,11,17,23-th traisobutyl-2,4,10,14,16,22-hexamethyl-1,7,13 is used, 19-tetraoxa-4,10,16,22-tetraaza-cy clotetracosan-3,6,9,12,15,18,21,24-octaone and 4-trifluoromethoxyphenylboronic acid as starting materials, the course of the reaction of the process according to the invention (2nd ) can be represented by the following formula:

For example, if 8,20-dibenzyl-5,11,17,23-tetraisobutyl-2,4,10, -14,16,22-hexamethyl-1,7,13,19-tetraoxa-4,10,16 is used, 22-tetraaza-cyclotetracosane-3,6,9, - 12,15,18,21,24-octaon (PF1022) as starting material and bromine / I, I-bis (trifluoroacetoxy) -iodobenzene as reagent, the reaction can proceed of the method (4a) according to the invention can be represented by the following formula:

If, for example, PF1022 is used as the starting material and iodine / I, I-bis (trifluoroacetoxy) iodobenzene is used as the reagent, the reaction sequence of process (4b) according to the invention can be represented by the following formula:

If, for example, PF1022E and perfluorobutyl fluoride are used as starting materials, the reaction sequence of process (4c) according to the invention can be represented by the following formula:

For example, 4- (14-benzyl-5,11,17,23-tetraisobutyl-4,8,10,16,20, - 22-hexamethyl-1,7,13,19-tetraoxa-4,10,16 is used , 22-tetraaza-cyclotetracosan-3,6,9,12,15, - 18,21,24-octaon-2-yl-methyl) phenyldiazonium chloride and trifluoromethanesulfonic acid as starting materials, the course of the reaction of process (4d) according to the invention can be carried out by the the following formula scheme can be reproduced:

The cyclo required to carry out process (2) according to the invention octadepsipeptides of formula (II) are partly new compounds. The new ver Bonds can be made according to methods (4a), (4b), (4c) or (4d).

EP-A 634 408 describes the preparation of compounds of the present formula (I), in which R ¹ and / or R ^{2 represent} amino, by catalytic reduction of the corresponding nitro-substituted compounds. Example 14 of EP-A 634 408 describes the conversion of the amino group into an OH residue by so-called diazo boiling. If the reaction described there is carried out at low temperatures (-50 ° C. to + 10 ° C.), preferably at -10 ° C. to + 5 ° C., the corresponding diazonium salts can be isolated. In this way, compounds of the formula (II) in which X ¹ and / or X ^{2 are} a diazonium radical can be obtained.

What is required to carry out processes (4a) and (4b) according to the invention Cyclooctadepsipeptide PF1022 is known from EP 382 173 A1 and can e.g. B. be produced by fermentation.

The cyclo required to carry out process (4c) according to the invention octadepsipeptides of formula (III) are e.g. B. as PF1022E and PF1022H from the JP 06184126 (cited in CA 122: 104043) or WO 97/11064 (cited in CA  126: 293615) or can be analogous to the methods described there produce.

The diazo required to carry out the method (4d) according to the invention Cyclooctadepsipeptides of the formula (V) can be prepared according to generally known methods Prepare methods by diazotizing the corresponding amino compounds, which are known for example from EP 634 408 A1, WO 97/11064 (cited in CA 126: 293615) or WO 97/02256 (cited in CA 126: 171904) or on there available in any way. To do this, one works either with inorganic Nitrites such as sodium nitrite in aqueous acids such as Hydrochloric acid, trifluoroacetic acid or tetrafluoroboric acid or with nitric acid alkyl esters such as B. isoamyl nitrite or butyl nitrite in anhydrous media such as Acetic acid containing hydrogen chloride.

Reagents for carrying out process (2) according to the invention are, for example, compounds of the formula (VII)

R ^1-1 -H (VII),

in which
R ^{1-1 stands} for one of the CC-linked heterocyclyl or optionally substituted alkenyl or alkynyl radical given there for R ¹ ,
Boron compounds of the formula (VIII)

in which
R ^{1-2 stands} for one of the CC-linked heterocyclyl or ge optionally substituted alkyl, alkenyl or aryl radicals given at R ¹ ,
R ⁹ and R ¹⁰ each represent hydrogen, isopropyl or together propylene, cycloocta-1,5-diyl or o-phenylene,
Tin compounds of formula (IX)

R ¹ -Sn (R ¹¹ ) ₃ (IX),

in which
R ^{1 has} the meaning given above and
R ^{11 represents} methyl, butyl or phenyl, or
Zinc cyanide.

The compounds of formula (VII) are generally known compounds of organic chemistry. The boron compounds of formula (VIII), especially the Boronic acids are known and some are commercially available, or according to known ones Methods can be produced [cf. e.g. B. Chem. Rev. 45, 2457 (1995); Pure appl. Chem. 66, 213 (1994); Synlett 1990, 221]. The tin compounds of the formula (IX) are known or can be produced using known methods [cf. e.g. B. M. Pereyre, J.-P. Quintard, A. Rahm: Tin In Organic Synthesis, Butterworths, London, 1987; Org. Chem. 54, 5064 (1989)].

Used as a catalyst for carrying out process (2) according to the invention for example compounds, especially complex compounds, of metals VIII. Subgroup of the periodic table, such as palladium or nickel preferably of palladium. Examples include: bis- (1,5-cyclooctadiene) - nickel (0), nickel (II) chloride, dichloro-bis (triphenylphosphine) nickel, nickel (II) acetyl  acetonate, palladium (II) acetate, chloride, dichlorobis (triphenylphosphine) palladium, Dichloro-bis [tri (2-methylphenyl) phosphine] palladium, diacetonitrilodichloropalladium, Bis [µ- (acetato-κO: κO ')] to [[2- [bis (2-methylphenyl) phosphino-κP] phenyl] methyl-κC] dipalladium, tris (dibenzylidene acetone) dipalladium, di (dibenzylidene acetone) palladium, Tetrakis (triphenylphosphine) palladium or one of the above Connections in com combination with a free complex-forming ligand such as triphenyl phosphine, tri-o-tolylphosphine, trifurylphosphine, bis (diphenylphoshino) ethane, bis (di phenylphoshino) propane, bis (diphenylphoshino) butane, diphenylphosphinoferrocene or triphenylarsine. Nickel (0) or nickel (II) compounds can be used as nickel catalysts bindings are used. The nickel (II) compounds can be in situ in counter were suitable ligands reduced to nickel (0) compounds, e.g. B. by Zinc powder. Copper is used as the cocatalyst in couplings with alkynes iodide, which can also be useful in reactions with tin compounds.

Process (2) according to the invention is optionally carried out in the presence of a Reaction auxiliary carried out. Suitable for this are: alkali metal halides, such as Lithium chloride, lithium bromide, cesium fluoride or acid binder. As an acid binders are preferably used in the reaction with boron compounds of the formula (VIII) Alkaline earth metal or alkali metal hydroxides, acetates, carbonates or hydro gene carbonates, such as sodium, potassium, barium or aminonium hy hydroxide, sodium, potassium, calcium or ammonium acetate, sodium, potassium or Ammonium carbonate, sodium hydrogen or potassium hydrogen carbonate, silver carbonate, phosphates such as trisodium or tripotassium phosphate, alkali fluorides, as in for example cesium fluoride, and also tertiary amines, such as trimethylamine, Triethylamine, tributylamine, ethyldiisopropylamine, N, N-dimethylaniline, N, N-Di methyl-benzylamine, pyridine, N-methylpiperidine, N-methylmorpholine, N, N-dimethyl aminopyridine, diazabicyclooctane (DABCO), diazabicyclonones (DBN) or diazabi cycloundecene (DBU). In the reaction compounds of formula (II), the amino Alkali nitrites such as sodium nitrite are substituted Diazotization used.  

Process (2) according to the invention is preferably carried out in the presence of a diluent be carried out. When reacting with boron compounds of the formula (VIII) water, organic solvents and any mixtures thereof come in Consideration. Examples include: aliphatic, alicyclic or aromatic Koh Hydrogen oils, such as petroleum ether, hexane, heptane, cyclohexane, methyl cyclohexane, benzene, toluene, xylene or decalin; halogenated hydrocarbons, such as for example chlorobenzene, dichlorobenzene, methylene chloride, chloroform, tetrachlor methane, dichloro, trichloroethane or tetrachlorethylene; Ethers such as diethyl, diiso propyl, methyl t-butyl, methyl t-amyl ether, dioxane, tetrahydrofuran, 1,2-dimeth oxyethane, 1,2-diethoxyethane, diethylene glycol dimethyl ether or anisole; Alcohols, such as methanol, ethanol, n- or i-propanol, n-, iso-, sec- or tert-butanol, ethanediol, Propane-1,2-diol, ethoxyethanol, methoxyethanol, diethylene glycol monomethyl ether, Diethylene glycol monoethyl ether; Water. When implementing connections the Formula (II), which are (diazotized) amines, become aqueous acids, such as Hydrochloric acid, trifluoroacetic acid or tetrafluoroboric acid, optionally in the presence a solubilizer, such as alcohols such as methanol. At The other reactions are dipolar aprotic as diluents Solvent advantageous. Examples include: ethers such as diethyl and diiso propyl, methyl t-butyl, methyl t-amyl ether, dioxane, tetrahydrofuran, 1,2-dimeth oxyethane, 1,2-diethoxyethane, diethylene glycol dimethyl ether or anisole; Ketones like Acetone, butanone, methyl isobutyl ketone or cyclohexanone; Nitriles, such as acetonitrile, Propionitrile, n- or i-butyronitrile or benzonitrile, amides such as formamide, N, N-Di methylformamide, N, N-dimethylacetarnide, N-methylformanilide, N-methylpyrrolidone or hexamethylphosphoric triamide; Sulfoxides such as dimethyl sulfoxide. Amines that Above specified as acid binders can be used in a larger Excess also serve as a diluent.

The process (2) according to the invention can also be carried out in a two-phase system such as, for example, methylene chloride / water, preferably using a suitable phase transfer catalyst. Examples of such catalysts are: tetrabutylammonium iodide, bromide or chloride, tributyl methylphosphonium bromide, trimethyl-C ₁₃ / C ₁₅ alkylammonium chloride or bromide, dibenzyldimethylammonium methyl sulfate, dimethyl-C ₁₂ / C ₁₄ -alkylbenzylammonium chloride Krone-5, 18-Krone-6 or tris- [2- (2-methoxyethoxy) ethyl] amine.

The reaction temperatures can be carried out when carrying out the process according to the invention Process (2) can be varied over a wide range. Generally works one at temperatures between 20 ° C and 200 ° C, preferably between 50 ° C and 150 ° C. In the case of an upstream diazotization, if appropriate, is first carried out at -20 ° C. worked up to + 30 ° C.

A bromination is carried out to carry out process (4a) according to the invention reagent needed. Bromine in the presence of I, I-bis (trifluoroacetoxy) iodobenzene.

The process (4a) according to the invention is preferably carried out in the presence of a ver performed fertilizer. Add water, organic solvents and any mixtures thereof. Examples include: aliphatic, alicyclic or aromatic hydrocarbons, such as petroleum ether, Hexane, heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin; halogenated hydrocarbons, such as chlorobenzene, dichlorobenzene, Methylene chloride, chloroform, carbon tetrachloride, dichloro, trichloroethane or tetra chlorethylene; Ethers, such as diethyl, diisopropyl, methyl t-butyl, methyl t-amyl ether, Dioxane, tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane, diethylene glycol dimethyl ether or anisole; Ketones such as acetone, butanone, methyl isobutyl ketone or Cyclohexanone; Nitriles, such as acetonitrile, propionitrile, n- or i-butyronitrile or benzo nitrile; Amides, such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylformanilide, N-methylpyrrolidone or hexamethylphosphoric triamide; N-oxides such as N-methylmorpholine-N-oxide; Esters such as methyl, ethyl or butyl acetate; Sulfoxides such as dimethyl sulfoxide; Sulfones such as sulfolane; Alcohols, such as methanol, Ethanol, n- or i-propanol, n-, i-, s- or t-butanol, ethanediol, propane-1,2-diol, eth oxyethanol, methoxyethanol, diethylene glycol monomethyl ether, diethylene glycol mo noethyl ether; Water.  

The reaction temperatures can be carried out when carrying out the process according to the invention Process (4a) can be varied over a wide range. Generally works one at temperatures between -50 ° C and + 50 ° C, preferably between -20 ° C and + 30 ° C.

To carry out process (4a) according to the invention, 0.5 to 5 mol of bromine are generally used per mol of PF1022. If the monobromo compound (X ^2-1 = H) is preferred, 0.5 to 1.0 mol is used, if the di-bromo compound (X ^2-1 = Br) is preferred, 3 to 5 mol of bromine are used. In general, 1.0 to 1.2 mol of I, I-bis (trifluoroacetoxy) iodobenzene are used per mol of bromine.

An iodination is used to carry out the method (4b) according to the invention reagent needed. For example, iodine in the presence of I, I-bis (trifluoroacetoxy) iodobenzene or iodine in the presence of alkali metal iodate, such as. B. Sodium iodate and in the presence of a protonic acid such as acetic acid or sulfuric acid or bis (pyridine) iodonium (I) tetrafluoroborate in the presence of a Protonic acid such as trifluoromethanesulfonic acid or hydrogen tetra fluoroborate (J. Org. Chem. 58, 2058 (1993)).

The process (4b) according to the invention is preferably carried out in the presence of a ver performed fertilizer. In addition, for the reaction with I, I-bis (trifluor acetoxy) iodobenzene e.g. B. all of the solvents listed in process (4a) in Be for those with iodate z. B. acetic acid and sulfuric acid.

The reaction temperatures can be carried out when carrying out the process according to the invention Process (4b) can be varied over a wide range. Generally works one when using I, I-bis (trifluoroacetoxy) iodobenzene at temperatures between -50 ° C and + 50 ° C, preferably between -20 ° C and + 30 ° C, when using iodate at temperatures between 0 ° C and + 100 ° C, preferably between 20 ° C and + 80 ° C.  

To carry out process (4b) according to the invention, 1 to 5 moles of iodine are generally used per mole of PF1022. If the monoiodo compound (X ^2-2 = H) is preferred, 1 to 5 mol of iodine and 2 to 10 mol of I, I-bis (trifluoroacetoxy) iodobenzene are used. If the diiodic compound (X ^2-2 = I) is preferred, 1.5 to 2 mol of iodine and 0.5 to 1.5 mol of iodate are used.

As an acid binder for carrying out the process (4c) according to the invention primarily organic bases come into question. For example, be called: Ter tertiary amines, such as trimethylamine, triethylamine, tributylamine, N, N-dimethylaniline, N, N-dimethylbenzylamine, pyridine, N-methylpiperidine, N-methylmorpholine, N, N-di methylaminopyridine, diazabicyclooctane (DABCO), diazabicyclonones (DBN) or Diazabicycloundecene (DBU).

Process (4c) is optionally carried out in the presence of a diluent carried out. Organic solvents and any mixtures are used for this of them into consideration. Examples include: aliphatic, alicyclic or aroma table hydrocarbons, such as petroleum ether, hexane, heptane, cyclo hexane, methylcyclohexane, benzene, toluene, xylene or decalin; halogenated coals Hydrogen, such as chlorobenzene, dichlorobenzene, methylene chloride, Chloroform, carbon tetrachloride, dichloro, trichloroethane or carbon tetrachloride; Ether, such as diethyl, diisopropyl, methyl t-butyl, methyl t-amyl ether, dioxane, tetrahydro furan, 1,2-dimethoxyethane, 1,2-diethoxyethane, diethylene glycol dimethyl ether or Anisole; as well as an excess of organic base itself.

The reaction temperatures can be carried out when carrying out the process according to the invention Process (4c) can be varied over a wide range. Generally works one at temperatures between -50 ° C and + 50 ° C, preferably between -20 ° C and + 30 ° C.

To carry out the process (4c) according to the invention, one sets per equivalent Hydroxy-substituted cyclooctadepsipeptide of the formula (III) in general 1 to  10 moles, preferably 1.2 to 5 moles of sulfonic acid derivative (IV), and 1 to 10 moles before draws in 1 to 5 moles of acid binder.

The reaction temperatures can be carried out when carrying out the process according to the invention Process (4d) can be varied over a wide range. Generally works one at temperatures between 50 ° C and 180 ° C, preferably between 60 ° C and 140 ° C. If necessary, one still irradiates with a light source, the UV radiation gives.

The fluorinated sulfonic acid of formula (VI) is generally in a larger Excess used.

The reactions of the processes according to the invention can be carried out at normal pressure or be carried out under increased pressure. Preferably, at normal pressure is working. Carrying out the reaction, working up and isolating the reaction pro Products are made according to generally known methods. The end products will be preferably by crystallization, chromatographic separation or by Ent Removal of the volatile constituents, if necessary in a vacuum, cleaned (see also the manufacturing examples).

The active substances are suitable for combating pathogenic endoparasites, which occur in humans and in animal husbandry and animal breeding in useful, breeding, zoo, laboratory, experimental and hobby animals, with favorable warm-blooded toxicity. They are effective against all or individual stages of development of the pests and against resistant and normally sensitive species. By combating the pathogenic endo parasites, illness, death and reduced performance (e.g. in the production of meat, milk, wool, skins, eggs, honey, etc.) are to be reduced, so that the use of the active compounds makes them more economical and easier animal husbandry is possible. Pathogenic endoparasites include cestodes, trematodes, nematodes, in particular:
From the order of the Pseudophyllidea z. E.g .: Diphyllobothrium spp., Spirometra spp., Schistocephalus spp., Ligula spp., Bothridium spp., Diphlogonoorus spp.

From the order of the Cyclophyllidea z. E.g .: Mesocestoides spp., Anoplocephala spp., Paranoplocephala spp., Moniezia spp., Thysanosmsa spp., Thysaniezia spp., Avitellina spp., Stilesia spp., Cittotaenia spp., Anhyra spp., Bertiella spp., Taenia spp., Echinococcus spp., Hydratigera spp., Davainea spp., Raillietina spp., Hymenolepsis spp., Echinolepsis spp., Echinocotyle spp., Diorchis spp., Dipylidium spp., Joyeuxiella spp., Diplopylidium spp.

From the subclass of Monogenea z. E.g .: Cyrodactylus spp., Dactylogyrus spp., Polystoma spp.

From the subclass of Digenea z. E.g .: Diplostomum spp., Posthodiplostomum spp., Schistosoma spp., Trichobilharzia spp., Ornithobilharzia spp., Austrobilharzia spp., Gigantobilharzia spp., Leucochloridium spp., Brachylaima spp., Echinostoma spp., Echinoparyphium spp., Echinochasmus spp., Hypoderaeum spp., Fasciola spp., Fasciolides spp., Fasciolopsis spp., Cyclocoelum spp., Typhloccelum spp., Paramphistomum spp., Calicophoron spp., Cotylophoron spp., Gigantocotyle spp., Fischoederius spp., Gastrothylacus spp., Notocotylus spp., Catatropis spp., Plagiorchis spp., Prosthogonismus spp., Dicrocoelium spp., Collyriclum spp., Nanophyetus spp., Opisthorchis spp., Clonorchis spp., Metorchis spp., Heterophyes spp., Metagonimus spp.

From the order of the Enoplida z. For example: Trichuris spp., Capillaria spp., Trichlomosoides spp., Trichinella spp.

From the order of the Rhabditia z. E.g. Micronema spp., Strongyloides spp.

From the order of Strongylida z. E.g. Stronylus spp., Triodontophorus spp., Oesophagodontus spp., Trichonema spp., Gyalocephalus spp., Cylindropharynx spp., Poteriostromum spp., Cyclococercus spp., Cylicostephanus spp., Oesophagostomum  spp., Chabertia spp., Stephanurus spp., Ancylostoma spp., Uncinaria spp., Bunostomum spp., Globocephalus spp., Syngamus spp., Cyathostoma spp., Metastrongylus spp., Dictyocaulus spp., Muellerius spp., Protostrongylus spp., Neostrongylus spp., Cystocaulus spp., Pneumostrongylus spp., Spicocaulus spp., Elaphostrongylus spp., Parelaphostrongylus spp., Crenosoma spp., Paracrenosoma spp., Angiostrongylus spp., Aelurostrongylus spp., Filaroides spp., Parafllaroides spp., Trichostrongylus spp., Haemonchus spp., Ostertagia spp., Marshallagia spp., Cooperia spp., Nematodirus spp., Hyostrongylus spp., Obeliscoides spp., Amidostomum spp., Ollulanus spp.

From the order of the Oxyurida z. E.g .: Oxyuris spp., Enterobius spp., Passalurus spp., Syphacia spp., Aspiculuris spp., Heterakis spp.

From the order of Ascaridia z. For example: Ascaris spp., Toxascaris spp., Toxocara spp., Parascaris spp., Anisakis spp., Ascaridia spp.

From the order of the Spirurida z. E.g .: Gnathostoma spp., Physaloptera spp., Thelazia spp., Gongylonema spp., Habronema spp., Parabronema spp., Draschia spp., Dracunculus spp.

From the order of the Filariida z. E.g. Stephanofilaria spp., Parafl1aria spp., Setaria spp., Loa spp., Dirofilaria spp., Litomosoides spp., Brugia spp., Wuchereria spp., Onchocerca spp.

From the group of the Gigantohynchida z. E.g. Filicollis spp., Moniliformis spp., Macracanthorhynchus spp., Prosthenorchis spp.

For example, the active compounds according to the invention have an excellent action against worms such as Haemonchus contortus, Trichostrongylus colubriformis, Nematospiroides dubius and Heterakis spumosa.  

The livestock and breeding animals include mammals such as B. cattle, horses, sheep, Pigs, goats, camels, water buffalos, donkeys, rabbits, fallow deer, reindeer, Fur animals such as B. mink, chinchilla, raccoon, birds such. B. chickens, geese, turkeys, Ducks.

Laboratory and experimental animals include mice, rats, guinea pigs, gold hamsters, dogs and cats.

The pets include dogs and cats.

The application can be prophylactic as well as therapeutic.

The active ingredients are used directly or in the form of suitable accessories riding enterally, parenterally, dermally, nasally, by treating the environment or with the help of active ingredient-containing shaped bodies such. B. strips, plates, tapes.

The enteral application of the active ingredients happens, for. B. orally in the form of powder, Suppositories, tablets, capsules, pastes, drinkers, granules, drenches, boluses, medi feed or drinking water. The dermal application happens for. B. in the form of Diving (dipping), spraying (spraying), bathing, washing, pouring (pour-on and spot-on) and powdering. Parenteral use happens e.g. B. in the form injection (intramuscular, subcutaneous, intravenous, intraperitoneal) or by Implants.

Suitable preparations are:
Solutions such as solutions for injection, oral solutions, concentrates for oral administration after dilution, solutions for use on the skin or in body cavities, infusion formulations, gels;
Emulsions and suspensions for oral or dermal use and for injection; semi-solid preparations;
Formulations in which the active ingredient is processed in an ointment base or in an oil in water or water in oil emulsion base;
solid preparations such as powders, premixes or concentrates, oranulates, pellets, tablets, boluses, capsules; Aerosols and inhalants, molded articles containing active ingredients.

Solutions for injection are administered intravenously, intramuscularly and subcutaneously.

Injection solutions are made by adding the active ingredient in a suitable Solvent is dissolved and possibly additives such as solubilizers, acids, Bases, buffer salts, antioxidants, preservatives can be added. The Solutions are sterile filtered and filled.

The following may be mentioned as solvents: Physiologically compatible solvents such as Water, alcohols such as ethanol, butanol, benzyl alcohol, glycerin, hydrocarbons substances, propylene glycol, polyethylene glycols, N-methylpyrrolidone, and mixtures of the same.

The active ingredients can optionally also be found in physiologically compatible plants Dissolve common or synthetic oils that are suitable for injection.

The following may be mentioned as solubilizers: solvents which dissolve the active ingredient in the Promote major solvents or prevent them from failing. Examples are polyvinyl pyrrolidone, polyoxyethylated castor oil, polyoxyethylated sorbitan esters.

Preservatives are: benzyl alcohol, trichlorobutanol, p-hydroxybenzoic acid ester, n-butanol.

Oral solutions are applied directly. Concentrates are made according to previous Ver applied orally to the application concentration. Oral solutions and  Concentrates are prepared as described above for the injection solutions, where when sterile work can be dispensed with.

Solutions for use on the skin are dripped on, spread on, rubbed in rubbed, sprayed on, sprayed on or by immersion (dipping, bathing or washing) upset. These solutions are the same as for the injection solutions wrote manufactured.

It may be advantageous to add thickeners during manufacture.

Thickeners are: inorganic thickeners such as bentonites, colloidal Silicic acid, aluminum monostearate, organic thickeners such as cellulose deri vate, polyvinyl alcohols and their copolymers, acrylates and metacrylates.

Gels are applied or spread onto the skin or into body cavities brings. Gels are made by using solutions similar to those used for injection described have been prepared with so much thickener added, that a clear mass with ointment-like consistency is created. As a thickener the thickeners specified above are used.

Pour-on formulations are poured onto limited areas of the skin or sprayed on, the active ingredient either penetrating the skin and acting systemically or spread over the surface of the body.

Pour-on formulations are made by placing the active ingredient in suitable skin compatible solvents or solvent mixtures dissolved, suspended or is emulsified. If necessary, other auxiliaries such as dyes, right sorptive substances, antioxidants, light stabilizers, adhesives added.

The following may be mentioned as solvents: water, alkanols, glycols, polyethylene glycols, Polypropylene glycols, glycerin, aromatic alcohols such as benzyl alcohol, phenyl ethanol, phenoxyethanol, esters such as ethyl acetate, butyl acetate, benzyl benzoate, ethers such as Alkylene glycol alkyl ethers such as dipropylene glycol monomethyl ether, diethylene glycol  mono-butyl ether, ketones such as acetone, methyl ethyl ketone, aromatic and / or aliphatic hydrocarbons, vegetable or synthetic oils, DMF, dimethyl acetamide, N-methylpyrrolidone, 2-dimethyl-4-oxy-methylene-1,3-dioxolane.

Dyes are all dyes approved for use on animals that are dissolved or can be suspended.

Resorption promoting substances are e.g. B. DMSO, spreading oils such as isopropyl myristate, Dipropylene glycol pelargonate, silicone oils, fatty acid esters, triglycerides, fatty alcohols.

Antioxidants are sulfites or metabisulfites such as potassium metabisulfate, ascorbic acid, Butylated hydroxytoluene, butylated hydroxyanisole, tocopherol.

Light stabilizers are e.g. B. substances from the class of benzophenones or novantisole acid.

Adhesives are e.g. B. cellulose derivatives, starch derivatives, polyacrylates, natural poly mers like alginates, gelatin.

Emulsions can be used orally, dermally or as an injection.

Emulsions are either water in oil or oil in water.

They are made by either the active ingredient in the hydrophobic or dissolved in the hydrophilic phase and this with the help of suitable emulsifiers and optionally other auxiliaries such as dyes, absorption-promoting substances, Preservatives, antioxidants, light stabilizers, viscosity-increasing substances, homogenized with the solvent of the other phase.

The following may be mentioned as the hydrophobic phase (oils): paraffin oils, silicone oils, natural vegetable oils such as sesame oil, almond oil, castor oil, synthetic triglycerides such as caprylic / capric acid biglyceride, triglyceride mixture with vegetable fatty acid of chain length C ₈ -C ₁₂ or other specially selected natural fatty acids, Partial glyceride mixtures of saturated or unsaturated fatty acids which may also contain hydroxyl groups, mono- and diglycerides of C ₈ / C ₁₀ fatty acids.

Fatty acid esters such as ethyl stearate, di-n-butyryl adipate, lauric acid hexyl ester, dipropylene glycol pelargonate, esters of a branched fatty acid of medium chain length with saturated fatty alcohols of chain length C ₁₆ -C ₁₈ , isopropyl myristate, isopropyl palmitate, caprylic / capric alcohol esters of the saturated fatty length C ₁₂ -C ₁₈ , isopropyl stearate, oleic acid oleyl ester, oleic acid decyl ester, ethyl oleate, lactic acid ethyl ester, waxy fatty acid esters such as artificial duckling gland fat, di butyl phthalate, adipic acid diisopropyl ester, the latter related ester mixtures and others

Fatty alcohols such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol, oleyl alcohol.

Fatty acids such as B. oleic acid and its mixtures.

The following can be mentioned as the hydrophilic phase:
Water, alcohols such as B. propylene glycol, glycerin, sorbitol and their mixtures.

The following may be mentioned as emulsifiers: nonionic surfactants, e.g. B. polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, sorbitan monostearate, glycerol monostearate, polyoxyethyl stearate, alkylphenol polyglycol ether;
ampholytic surfactants such as di-Na-N-lauryl-β-iminodipropionate or lecithin;
anionic surfactants such as sodium lauryl sulfate, fatty alcohol ether sulfates, mono / dialkyl polyglycol ether orthophosphoric acid ester monoethanolamine salt;
cationic surfactants such as cetyltrimethylammonium chloride.

The following may be mentioned as further auxiliaries: viscosity-increasing agents and the emulsion stabi lizing substances such as carboxymethyl cellulose, methyl cellulose and other cellulose and Starch derivatives, polyacrylates, alginates, gelatin, gum arabic, polyviryl pyrrolidone, polyvinyl alcohol, copolymers of methyl vinyl ether and maleic acid hydride, polyethylene glycols, waxes, colloidal silica or mixtures of the led fabrics.

Suspensions can be used orally, dermally or as an injection. you will be prepared by optionally taking the active ingredient in a carrier liquid Addition of other auxiliary substances such as wetting agents, dyes, absorption-promoting substances, Preservatives, antioxidants, sunscreen suspended.

Carrier liquids are all homogeneous solvents and solvents called mix.

The surfactants specified above may be mentioned as wetting agents (dispersants).

Further additives mentioned are those mentioned above.

Semi-solid preparations can be administered orally or dermally. You under differ only from the suspensions and emulsions described above their higher viscosity.

The active ingredient is used with suitable carriers to produce solid preparations optionally mixed with additives and in the desired shape brought.

All physiologically compatible solid inert substances may be mentioned as carriers. All such serve inorganic and organic substances. Inorganic substances are e.g. B. Common salt, carbonates such as calcium carbonate, hydrogen carbonates, aluminum oxides, Silicas, clays, precipitated or colloidal silicon dioxide, phosphates.  

Organic substances are e.g. B. sugar, cellulose, food and feed such as Milk powder, animal meal, cereal flour and meal, starches.

Excipients are preservatives, antioxidants, dyes that are already on have been listed above.

Other suitable auxiliaries are lubricants and lubricants such as. B. Magnesium stearate, stearic acid, talc, bentonite, decay promoting substances such as starch or cross-linked polyvinylpyrrolidone, binders such. B. starch, gelatin or linear polyvinylpyrrolidone and dry binders such as microcrystalline cellulose.

The active substances can also be mixed with synergists or with other active substances that act against pathogenic endoparasites. Such active ingredients are e.g. B. L-2,3,5,6-tetrahydro-6-phenyl-imidazolothiazole, Benzimidazole carbamates, praziquantel, pyrantel, febantel.

Ready-to-use preparations contain the active substance in concentrations of 10 ppm to 20% by weight, preferably from 0.1 to 10% by weight.

Preparations that are diluted before use contain the active ingredient in Concentrations from 0.5 to 90% by weight, preferably from 5 to 50% by weight.

In general, it has proven advantageous to use amounts of about 1 to 100 mg Active ingredient per kg body weight per day to achieve effective results pass.

The production and use of the active compounds according to the invention or Intermediates are shown in the examples below.

Manufacturing examples example 1

Preparation of the diiod derivative of PF1022

PF1022 (0.95 g; 1 mmol) was suspended in glacial acetic acid (4 ml) under argon. After adding sulfuric acid (conc .; 0.44 ml) sodium iodate (166 mg; 0.84 mmol) and iodine (406 mg; 1.60 mmol) were added. The mixture was heated to 70 ° C. in an oil bath with vigorous stirring. After 7 hours, the mixture was allowed to cool and a little chloroform was added to dilute it. The reaction mixture was washed with sodium sulfite solution (30%, aq.). After the phases had been separated, the aqueous phase was neutralized with sodium carbonate and extracted again with chloroform. The combined organic phases were washed with sodium bicarbonate solution (sat., Aq.), Then with sodium chloride solution (sat., Aq.). After drying (magnesium sulfate) the solvent was distilled off. The remaining oil was purified by column chromatography (silica gel; ∅ × l = 5 cm × 50 cm; cyclohexane / ethyl acetate = 4 + 1). 0.9 g (75% of theory) of a colorless solid was obtained. After semi-prep. HPLC (acetonitrile / H ₂ O = 75 + 25) gave 0.6 g of the isomeric bis-iodobenzyl compounds.
FAB-MS: m / z (nominal mass): 1223 (M + Na⁺); 1201 (M + H⁺)
Mp: 84 ° C

Example 2

Preparation of the mono-iodine derivative of PF1022

PF1022 (0.96 g; 1 mmol) was dissolved in chloroform (25 ml) under argon. I, I-bis (trifluoroacetoxy) iodobenzene (= PhIL ₂ ) (2.76 g; 6.44 mmol) and then iodine (1.10 g; 4 mmol) were metered in at 0.degree. The mixture was allowed to warm to room temperature. After 7 days at room temperature, the reaction solution was poured into sodium sulfite solution (30%, aq.). The phases were separated.

After the phases had been separated, the aqueous phase was neutralized with sodium carbonate and extracted again with chloroform. The combined organic phases were washed with sodium bicarbonate solution (sat., Aq.), Then with sodium chloride solution (sat., Aq.). After drying (magnesium sulfate), the solvent was distilled off. The remaining oil was purified by means of column chromatography (silica gel; ∅ × l = 5 cm × 50 cm; cyclohexane / ethyl acetate = 4 + 1). 0.44 g of colorless solid was obtained by means of semi-prep. HPLC (acetonitrile / H ₂ O = 75 + 25) isolated 0.2 g of the isomeric mono-iodobenzyl compounds.
FAB-MS: m / z: 1097 (M + Na⁺); 1075 (M + H⁺)
Mp: 95 ° C

Example 3

Preparation of the dibromo derivative of PF1022

PF1022 (1.9 g; 2 mmol) was dissolved in chloroform (30 ml) under argon. PhIL ₂ (3.6 g; 8.4 mmol) was metered in at 0 ° C. and then bromine (1.28 g; 8 mmol) was added dropwise. The mixture was allowed to warm to room temperature. After five days at room temperature, the reaction mixture was poured into sodium sulfite solution (30% aq.). The phases were separated. The aqueous phase was extracted with chloroform. For neutralization, the aqueous phase was mixed with sodium carbonate and extracted again with chloroform. The combined organic phases were washed with sodium hydrogen carbonate solution (sat., Aq.), Then with sodium chloride solution (sat., Aq.). After drying (magnesium sulfate) the solvent was distilled off. The remaining oil was purified by column chromatography (silica gel; ∅ × l = 5 cm × 50 cm; ethyl acetate / cyclohexane = 1 + 4). 1.24 g (62% of theory) of the isomeric bis-bromobenzyl compounds were obtained.
FAB-MS m / z: 1127 (M + Na⁺), 1105 (M + H⁺)
Mp: 99 ° C

Example 4

Preparation of the monobromo derivative of PF1022

The reaction and working up were carried out analogously to Example 3, but in the presence of 1.5 eq bromine and 1.6 eq PhIL ₂ (see above).

Separation of still existing PF1022 by semi-prep. HPLC (acetonitrile / - H ₂ O = 70 + 30) gave 0.3 g of the isomeric monobromobenzyl compounds.
FAB-MS m / z: 1049 (M + Na⁺)
Mp: 136 ° C

Example 5

Preparation of the monotriflate derivative of PF1022

Trifluoromethanesulfonic anhydride (79.1 μl; 135.4 mg; 0.22 mmol) was added dropwise to a solution of the monohydroxy compound PF1022E (386 mg; 0.40 mmol) in dry pyridine (2 ml) at -20 ° C. The mixture was allowed to warm to 0 ° C. and stirred at this temperature for 24 h. After checking by TLC, the mixture was poured into water and extracted with ethyl acetate. The combined organic phases were washed with 10% hydrochloric acid, water and saturated sodium chloride solution, dried over magnesium sulfate and then concentrated. The residue was purified by column chromatography (silica gel; ∅ × l = 5 cm × 50 cm; cyclohexane / ethyl acetate = 4 + 1; conditioning: + 1% trifluoroacetic acid). 304.4 mg (73% of theory) of 20-benzyl-5,11,17,23-tetraisobutyl-2,4,10,14,16,22-hexa methyl-8- (4-trifluoromethylsulfonyloxybenzyl) -1,7,13,19-tetraoxa-4,10,16,22-tetraaza tetracosan-3,6,9,12,15,18,21,24-octaone.
ESI-MS: m / z (nominal mass): 1097 (M + H⁺), 1119 (M + Na⁺)

Example 6

Preparation of the bis (1-ethoxycarbonylethen-2-yl) derivative of PF1022

The mixture of the isomeric bis-iodobenzyl compounds from example 1 (0.87 g; 0.72 mmol) and ethyl acrylate (0.36 g; 3.6 mmol) were introduced under argon. Tributylamine (0.4 g; 2.20 mmol) and palladium (II) acetate (41 mg; 25 mol%) were added with stirring at room temperature. The reaction was carried out at 100 ° C for 27 hours. For working up, it was taken up in 10 ml of chloroform. The organic phase was washed with H ₂ O and then dried (magnesium sulfate). Further purification by column chromatography (1st cyclohexane; 2nd cyclohexane / ethyl acetate = 3 + 1; 3rd cyclohexane / ethyl acetate = 1 + 1) gave 0.5 g of crude product. Using semipreparative HPLC (acetonitrile / H ₂ O = 80 + 20), 0.14 g of product twice substituted by 1-ethoxycarbonylethen-2-yl was isolated.
FAB-MS: m / z: 1167 (M + Na⁺)

Example 7

Reaction of the diiodic derivative of PF1022 with 2-methylbut-3-in-2-ol

The mixture of the isomeric bis-iodobenzyl compounds from example 1 (0.80 g; 0.67 mmol) and 2-methylbut-3-yn-2-ol (0.22 g; 2.6 mmol) submitted. Triethylamine (1 ml), bis (triphenylphosphine) palladium dichloride (94 mg; 20 mol%) and copper iodide (19 mg; 15 mol%) were added with stirring. The reaction was carried out at 80 ° C for 15 hours. For working up, it was taken up in 10 ml of chloroform. The organic phase was washed with water and then dried (magnesium sulfate). Further purification by column chromatography (cyclohexane / ethyl acetate = 1 + 1) gave 0.5 g of crude product. Using semipreparative HPLC (acetonitrile / H ₂ O = 70 + 30), mono- and bis-substitution products were separated.
Bis (3-hydroxy-3-methyl-1-butyn-1-yl) derivative (6-1):
FAB-MS: m / z: 1135 (M + Na⁺) mp: 179 ° C
Mono (3-hydroxy-3-methyl-1-butyn-1-yl) derivative (6-2):
FAB-MS: m / z: 1053 (M + Na⁺) mp: 85 ° C

Example 8

Preparation of the bis (4-methoxyphenyl) derivative of PF1022

The mixture of the isomeric bis-iodobenzyl compounds from example 1 (0.50 g; 0.42 mmol) and p-methoxyphenylboronic acid (0.14 g; 0.92 mmol) was dissolved in toluene (4 ml) under argon. With stirring, 2M sodium bicarbonate solution (0.6 ml) and tetrakis (triphenylphosphine) palladium (100 mg; 20 mol%) were added at room temperature. After 18 h at 80 ° C by means of qual. HPLC no longer detectable educt. For working up, it was taken up in 10 ml of chloroform. The organic phase was washed with water and then dried (magnesium sulfate). Further purification by column chromatography (cyclohexau / ethyl acetate = 1 + 1) gave 0.42 g (85% of theory) of bis-methoxybiphenyl compound.
FAB-MS: m / z: 1183 (M + Na⁺)

Example 9

Preparation of the dicyano derivative of PF1022

The mixture of the isomeric bis-bromobenzyl compounds from Example 3 (0.87 g; 0.79 mmol) and zinc cyanide (0.11 g; 0.9 mmol) was dissolved in dimethylformamide (5 ml) under argon. Tetrakis (triphenylphosphine) palladium (0.137 g; 15 mol%) was added with stirring at room temperature. After 6 h at 80 ° C was worked up. For working up, it was diluted with toluene. The organic phase was washed with ammonia solution and then dried (magnesium sulfate). Further purification by column chromatography (cyclo hexane / ethyl acetate = 2 + 1) gave 0.5 g of bis-cyanobenzyl compound.
FAB-MS: m / z: 1021 (M + Na⁺)

Example 10

Preparation of the bis (cyanoethenyl) derivative of PF1022

Under an argon atmosphere, 8,20-bis (4-aminobenzyl) -5,11,17,23-tetraisobutyl-2,4,10,14,16,22-hexamethyl-1,7,13,19 -tetraoxa-4,10,16,22-tetraaza-cyclotetra cosan-3,6,9,12,15,18,21,24-octaone (979.2 mg; 1.0 mmol) in tertrafluoroboric acid (653 µl, 5.0 mmol), water (1.5 ml) added and diazotized at 0 ° C. by adding a sodium nitrite solution (141.5 mg; 2.05 mmol in 0.5 ml degassed water). After stirring at 0 ° C. for 30 min, methanol (4 ml), acrylonitrile (163.3 μl; 212.2 mg; 4.0 mmol) and palladium (II) acetate (9 mg) were added, followed by 1-2 h cooked under reflux. After TLC control, the filter was filtered through Cellite® filter aid, washed with dichloromethane and the filtrate evaporated in vacuo. Column chromatography (silica gel; ∅ × l = 2.5 cm × 32 cm; cyclohexane / ethyl acetate = 1 + 1) gave 370 mg (35% of theory) of 8,20-bis- [4- (2-cyanoethenyl ) benzyl] -5,11,17,23-tetraisobutyl-2,4,10,14,16,22-hexamethyl-1,7,13,19-tetra oxa-4,10,16,22-tetraaza-cyclotetracosane -3,6,9,12,15,18,21,24-octaon.
ESI-MS: m / z (nominal mass): 1053 (M + H⁺)

Examples of use Example A Anthelmintic activity in the mouse

Male mice of the strain SPF / CFWI, 16-18 g body weight, were used in all experiments. 5 animals were kept together in Makrolon® cages (polycarbonate) and received water and "Sniff ''" rat food ad libitum. Mice were mixed infected with the nematodes Nematospiroides dubius (= Heligmosomoides polygyrus) and Heterakis spumosa. The infection material of the L3 larvae of N. dubius worms was isolated from the mouse colon 35-42 days after infection and incubated at 27 ° C. for 3 weeks. Test substances (1 g) were dissolved or suspended in the Cremophor EL emulsifier. 0.5 ml of the solution or suspension was applied once per day for 20 g of mouse for 4 consecutive days. A dose of 100 mg / kg was given to a mouse. The mixed infection of the mouse was gradual. She was first infected orally with 90 embryonic H. spumosa eggs. 27 days later 60-70 filariform larvae of N. dubius were applied. Treatment with the substances started on the 46th day after infection and ended on the 49th day. After a further 8 days, the mice were killed with CO ₂ and dissected. H. spumosa were isolated from the caecum and colon and counted microscopically. The N. dubius worms were counted from a squeeze preparation of the duodenum. If no parasites were visible in the specimens, this gave a rating of 3.

In this test, e.g. B. the following compounds have the stated effect:

Example B Anthelmintic effectiveness in sheep

Merino or Schwarzkopf sheep, 25-35 kg body weight, were experimental infected with 5000 Haemonchus contortus L3 larvae and with the test substances be acts at the end of the prepatent period of the parasites (3-4 weeks). The test substances were administered orally using gelatin capsules. In the case of Trichosfrongylus colubriformis was infected with 12,000 L3 larvae. The anthelmintic effectiveness was measured by reducing the number of eggs excreted in the feces. To this Purpose was freshly obtained feces according to the common McMaster method processed and the number of eggs was determined per gram of faeces. The egg numbers were in regular intervals (3-4 days) before and after treatment for 6-8 weeks certainly. Over 95% egg reduction is referred to as 3 in the test.  

In this test, e.g. B. the following compounds have the stated effect:

Claims (7)

1. Cyclooctadepsipeptides of the formula (I)
in which
R ^{1 is} cyano, CC-linked heterocyclyl or optionally substituted alkenyl, alkynyl or aryl and
R ^{2 represents} hydrogen or the same radical as R ¹ . 2. A process for the preparation of the compounds of formula (I) according to claim 1
in which
R ^{1 is} cyano, CC-linked heterocyclyl or optionally substituted alkenyl, alkynyl or aryl and
R ^{2 represents} hydrogen or the same radical as R ¹ ,
characterized in that compounds of the formula (II)
in which
X ^{1 represents} bromine, iodine, -O-SO ₂ -R ^f , amino or -N ₂ ⁺ (X ³ ) ⁻, wherein
R ^{f represents} fluorinated C ₁ -C ₄ alkyl and
X ^{3 represents} a diazonium salt stabilizing anion and
X ^{2 represents} hydrogen or the same radical as X ¹ ,
with a suitable reagent which splits off the group R ¹ in the presence of a transition metal catalyst with CC linkage. 3. Cyclooctadepsipeptides of the formula (II)
in which
X ^{1 is} bromine, iodine, -OSO ₂ R ^f - where R ^{f is} fluorinated C ₁ -C ₄ alkyl, and
X ^{2 represents} hydrogen or the same radical as X ¹ . 4. A process for the preparation of compounds of formula (II) according to claim 3
in which
X ^{1 is} bromine, iodine, -OSO ₂ R ^f - where R ^{f is} fluorinated C ₁ -C ₄ alkyl, and
X ^{2 represents} hydrogen or the same radical as X ¹ , characterized in that

• a) in the case of bromo-substituted cyclooctadepsipeptides of the formula (II-a)
  in which
  X ^{2-1 represents} hydrogen or bromine,
  the cyclooctadepsipeptide of the following formula, designated PF1022
  brominated or
• b) in the case of iodinated cyclooctadepsipeptides of the formula (II-b)
  in which
  X ^{2-2 represents} hydrogen or iodine,
  iodines the cyclooctadepsipeptide designated PF1022 or
• c) in the case of sulfonic acid cyclooctadepsipeptide esters of the formula (II-c)
  in which
  R ^{f represents} fluorinated C ₁ -C ₄ alkyl and
  X ^{2-3 stands} for hydrogen or for -O-SO ₂ -R ^f
  hydroxy-substituted cyclooctadepsipeptides of the formula (III)
  in which
  X ^{3 represents} hydroxy or hydrogen,
  with sulfonic anhydrides or halides of the formula (IV)
  R ^f -SO ₂ -Y (IV),
  in which
  Y represents -O-SO ₂ -R ^f , F or chlorine, where R ^{f represents} fluorinated C ₁₄ alkyl,
  in the presence of an acid binder, or
• d) in the case of sulfonic acid cyclooctadepsipeptide esters of the formula (II-c), diazotized amino-substituted cyclooctadepsipeptide of the formula (V)
  in which
  X ^{4 represents} -N ₂ ⁺ (X ³ ) ^- or hydrogen,
  X ^{3 represents} a diazominium salt stabilizing anion,
  in the presence of a sulfonic acid of formula (VI)
  HO-SO ₂ -R ^f (VI),
  in which R ^{f has} the meaning given above,

implements. 5. Use of cyclooctadepsipeptides of the formula (I) according to claim 1 for Combating helminths in human and veterinary medicine. 6. Use of cyclooctadepsipeptides of formula (I) according to claim 1 for the production of agents for controlling endoparasites in the Human and veterinary medicine.   7. Agent for combating endoparasites characterized by a content of cyclooctadepsipeptides of formula (I) according to claim 1 in addition Extenders and diluents as well as any usual additives.